1. Field of the Invention
The present invention is directed to new cephem derivatives represented by the general formula ##STR3## in which the Acyl substituent is a group of the formula ##STR4## where Ar is a substituted phenyl or optionally substituted naphthyl or benzthiazolyl group and A is a substituted-pyridinium group. The derivatives are gram-positive antibiotics, especially useful in the treatment of diseases caused by methicillin-resistant Staphylococcus aureus (also referred to below as MRSA or methicillin-resistant S. aureus).
2. Description of the Prior Art
The cephalosporin class of .beta.-lactam antibiotics is frequently employed in the treatment of diseases caused by a wide variety of bacteria because they are generally both effective and nontoxic. Several generations of cephalosporins have been developed over the years, and there are now suitable commercially available cephalosporins for most types of pathogenic bacteria.
One notable exception to the above are the so-called methicillin-resistant strains of Staphylococcus aureus (MRSA) which have emerged as a serious problem, particularly in hospitals and long-term care facilities.
During the late 1950's the penicillin derivative, methicillin, was introduced to treat penicillinase-resistant strains of S. aureus. Since that time, methicillin-resistant strains of S. aureus have been observed and today such strains are a major source of infectious disease in hospital settings. Such hospital-acquired (i.e. nosocomial) infections, especially in burn units and intensive care wards, frequently cause life-threatening disease, including pneumonia, bacteremia and endocarditis. The number of effective therapeutic agents against MRSA is extremely limited.
The .beta.-lactam antibiotics, including those of the cephalosporin class, have been notably ineffective against MRSA. At the present time, intravenous vancomycin is the antibiotic of choice for the treatment of infections caused by such bacteria. The occasional failure of patients with severe MRSA infection to respond to vancomycin therapy, the belief that significant clinical resistance to vancomycin will eventually develop, and the side effects associated with vancomycin, e.g. ototoxicity and nephrotoxicity, have led to a search for alternative antibiotics to vancomycin therapy. One object of the present invention is to provide cephalosporin derivatives which are effective against MRSA infections and yet have a better side-effect profile than vancomycin.
The literature discloses a vast number of cephem derivatives having a wide variety of C-3 and C-7 substituents. Among the references directed to compounds having 3-pyridiniummethyl substituents and 7-substituents of the type ##STR5## where Ar is an aromatic group are the following: U.K. Patent 1,350,238 discloses the cephems of the formula ##STR6## wherein the aminomethyl substituent may be at the ortho-, meta- or para- position of the phenyl group as being useful in the treatment of infectious diseases caused by gram-positive and gram-negative bacteria.
U.S. Pat. No. 4,056,676 discloses cephem derivatives of the general formula ##STR7## where Z is hydrogen or fluorine; and when Z is hydrogen, each of X and Y is hydrogen or chlorine selected so that the phenyl ring is substituted with 1 or 2 chlorine atoms and so that when one chlorine atom is present said chlorine atom is in the 3-position, and when two chlorine atoms are present said chlorine atoms are in the 3,4-, the 3,5- or the 2,5-positions; and when Z is fluorine, said fluorine is in the 3- or 4-positions of the phenyl ring and each of X and Y is hydrogen or chlorine selected so that when the phenyl ring is substituted with 1 or 2 chlorine atoms, one of the chlorine atoms is in the 3- or 4-position of the phenyl ring; R.sup.1 is hydrogen, dicyclohexylamine, or a pharmaceutically acceptable cation; and R is, inter alia, N-pyridino. Among the compounds specifically disclosed are those of the formulae: ##STR8## The compounds disclosed are said to be useful for treating and inhibiting the growth of MRSA organisms.
The cephalosporin derivative of the formula ##STR9## is disclosed in Antimicrobial Agents and Chemotherapy--1966, pg. 573-580 at page 576 (Compound No. 48).
J. Antibiotics, 26(12), 737-744, 1973, discloses the compound of the formula ##STR10##
U.K. Patent 998,265 discloses cephem derivatives of the general formula ##STR11## in which R.sup.1, taken alone, is --OH, C.sub.1 -C.sub.8 acyloxy, or tertiaryamino, R.sup.2 is --OH when R.sup.1 is --OH, R.sup.2 is --OH when R.sup.1 is C.sub.1 -C.sub.8 acyloxy, R.sup.2 is --O-- when R.sup.1 is tertiaryamino, R.sup.1 and R.sup.2, when taken together, are --O--, R.sup.3 and R.sup.4 represent hydrogen, alkyl radicals having from 1 to 6 carbon atoms, alkenyl radicals having from 2 to 6 carbon atoms, cycloalkyl radicals having from 5 to 7 carbon atoms, or alkoxyalkyl radicals having from 2 to 6 carbon atoms; n represents 0 to 4; and R.sup.5 represents an alkyl radical having from 1 to 6 carbon atoms, an alkenyl or alkynyl radical having from 2 to 6 carbon atoms, a cycloalkyl radical having 5 or 6 carbon atoms, phenyl, .beta.-furyl, .beta.-thienyl, thienyl, or naphthyl, or a fluoro, chloro, bromo, nitro, trifluoromethyl, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkylmercapto, or C.sub.1 -C.sub.4 alkoxy substitution product of such radicals.
U.K. Published Application No. 2,007,221 A discloses cephalosporin derivatives of the formula ##STR12## wherein Y is hydrogen, chlorine, bromine, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy; Z is a bond, oxygen or sulfur; W is hydrogen, methyl, amino, hydroxy, SO.sub.3 H or COOR.sub.4 wherein R.sub.4 is hydrogen or 5-indanyl with the proviso that when Z is oxygen or sulfur, W is other than hydroxy; R.sub.1 is hydrogen or methoxy; R.sub.2 is hydrogen, acetoxy, 1,3,4-thiadiazol-2-ylthio, 5-methyl-1,3,4-thiadiazol-2-ylthio, tetrazol-5-ylthio, 1-methyltetrazol-5-ylthio, 1,3,4-oxadiazol-2-ylthio, 5-methyl-1,3,4-oxadiazol-2-ylthio, 1,3,4-triazol-2-ylthio, 5-methyl-1,3,4-triazol-2-ylthio, 1,2,3-triazol-5-ylthio, pyridinium or 4-aminocarbonylpyridinium; R.sub.3 is hydrogen, a negative charge when R.sub.2 is pyridinium or 4-aminocarbonylpyridinium, a cation of an alkali metal or an alkaline earth metal, ammonium or organic ammonium cations, C.sub.1 -C.sub.4 alkyl, (C.sub.2-5 alkanoyloxy)methyl, (C.sub.2-5 alkanoylamino)methyl, [C.sub.2-5 alkanoyl (C.sub.1-4 alkyl)amino]methyl, (C.sub.1-4 alkoxy)-carbonylaminomethyl, (C.sub.1-4 alkoxy)carbonyl(C.sub.1-4 alkyl)-amino-methyl, p-(C.sub.2 -alkanoyloxy)benzylamino(C.sub.2-15 alkanoyloxy)methyl, (C.sub.1-4 alkyl)amino(C.sub.2-15 alkanoyloxy)methyl or di(C.sub.1-4 alkyl)amino(C.sub.2-15 alkanoyloxy)methyl; and pharmaceutically acceptable salts thereof.
U.K. Patent 1,073,996 discloses cephem derivatives of the formula ##STR13## wherein R.sub.1 is a lower alkyl, lower alkanoylamino, pyridyl, aryl, halo, and/or nitro substituted aryl radical; R.sub.2 is an acetoxy, pyridinium, amino-pyridinium, imidazolium or methyl-imidazolium group; X is an oxygen or sulfur atom; Y is a nitrogen atom or the group .dbd.CH--; Z is the group --CH.sub.2 -- or --CH.sub.2 --CH.sub.2 --; and M is a hydrogen atom, a pharmaceutically acceptable non-toxic cation or an anionic charge.
U.S. Pat. No. 3,217,000 discloses cephem derivatives of the formula ##STR14## wherein Thi is 2-thienyl or 3-thienyl and R is a substituent at the 3 or 4 position of the pyridino ring selected from the group consisting of cyano, carboxy, carbamyl, N-methylcarbamyl, carbo (C.sub.1 -C.sub.4 alkoxy), hydroxy and (C.sub.1 -C.sub.4)alkanoyl; and the salts thereof with pharmaceutically acceptable acids.